IκBNS induces Muc5ac expression in epithelial cells and causes airway hyper-responsiveness in murine asthma models.

BACKGROUND: In allergic asthma, environmental allergens including house dust mite (HDM) trigger pattern recognition receptors and activate downstream signaling pathways including NF-κB pathways not only in immune cells but also in airway epithelial cells. Recent studies have shown that NF-κB activation is regulated positively or negatively depending on the cellular context by IκBNS (encoded by the gene Nfkbid), one of atypical IκB proteins, in the nucleus. Therefore, we hypothesized that IκBNS expressed in immune cells or epithelial cells is involved in the regulation of asthmatic responses. AIM: To determine the roles of IκBNS in HDM-induced asthmatic responses. METHODS: Roles of IκBNS in HDM-induced airway inflammation and airway hyper-responsiveness (AHR) were examined by using IκBNS-deficient (Nfkbid-/- ) mice. Roles of IκBNS expressed in hematopoietic cells and nonhematopoietic cells were separately evaluated by bone marrow chimeric mice. Roles of IκBNS expressed in murine tracheal epithelial cells (mTECs) were examined by air-liquid interface culture. RESULTS: House dust mite-induced airway inflammation and AHR were exacerbated in mice lacking IκBNS in hematopoietic cells. In contrast, HDM-induced airway inflammation was exacerbated, but AHR was attenuated in mice lacking IκBNS in nonhematopoietic cells. The induction of Muc5ac, a representative mucin in asthmatic airways, was reduced in Nfkbid-/- mTEC, whereas the induction of Spdef, a master regulator of goblet cell metaplasia, was not impaired in Nfkbid-/- mTEC. Moreover, IκBNS bound to and activated the MUC5AC distal promoter in epithelial cells. CONCLUSION: IκBNS is involved in inducing Muc5ac expression in lung epithelial cells and causing AHR in HDM-induced asthma models.

2-Chloroacetamidine, a novel immunomodulator, suppresses antigen-induced mouse airway inflammation.

BACKGROUND: Citrullination is a presently under-recognized posttranslational protein modification catalyzed by PAD enzymes. Immune responses to citrullinated neo-epitopes are identified in a growing number of inflammatory and autoimmune diseases. However, the involvement of hypercitrullination in the pathogenesis of bronchial asthma is still unknown. METHODS: As main experimental tool, we examined the effect of 2-chloroacetamidine (2CA), a PAD enzyme inhibitor, on OVA-immunized and airway-challenged BALB/c mice; a commonly used model of allergic airway inflammation. We also measured the effect of 2CA on ex vivo lymphocytes and cell lines. RESULTS: In vivo, 2CA dramatically suppressed lung tissue hypercitrullination, inflammatory cell recruitment, and airway-Th2 cytokine secretion. 2CA also suppressed systemic OVA-specific and total IgE production dramatically, effectively preventing de novo and diminishing established disease without measurably impacting general immunocompetence. In vitro, 2CA markedly inhibited the proliferation of mouse and human T cells with cell cycle block and apoptosis during a limited, postactivation phase. CONCLUSIONS: 2CA acts as narrow-spectrum immunosuppressant that selectively targets lymphocyte populations involved in active inflammatory tissue lesions. If hypercitrullination is generated in patients with asthma, 2CA may represent a novel disease modulator for human asthmatics/allergic diseases.

Additional strange hadrons from QCD thermodynamics and strangeness freezeout in heavy ion collisions.

We compare lattice QCD results for appropriate combinations of net strangeness fluctuations and their correlations with net baryon number fluctuations with predictions from two hadron resonance gas (HRG) models having different strange hadron content. The conventionally used HRG model based on experimentally established strange hadrons fails to describe the lattice QCD results in the hadronic phase close to the QCD crossover. Supplementing the conventional HRG with additional, experimentally uncharted strange hadrons predicted by quark model calculations and observed in lattice QCD spectrum calculations leads to good descriptions of strange hadron thermodynamics below the QCD crossover. We show that the thermodynamic presence of these additional states gets imprinted in the yields of the ground-state strange hadrons leading to a systematic 5-8 MeV decrease of the chemical freeze-out temperatures of ground-state strange baryons.

An in vitro demonstration of CMOS-based optoelectronic neural interface device for optogenetics.

A CMOS-based neural interface device equipped with an integrated micro light source array for optogenetics was fabricated and demonstrated. A GaInN LED array formed on sapphire substrate was successfully assembled with a multifunctional CMOS image sensor that is capable of on-chip current injection. We demonstrated a functionality of light stimulation onto ChR2-expressed cells in an in vitro experiment. A ChR2-expressed cell were successfully stimulated with the light emitted from the fabricated device.

Strangeness at high temperatures: from hadrons to quarks.

Appropriate combinations of up to fourth order cumulants of net strangeness fluctuations and their correlations with net baryon number and electric charge fluctuations, obtained from lattice QCD calculations, have been used to probe the strangeness carrying degrees of freedom at high temperatures. For temperatures up to the chiral crossover, separate contributions of strange mesons and baryons can be well described by an uncorrelated gas of hadrons. Such a description breaks down in the chiral crossover region, suggesting that the deconfinement of strangeness takes place at the chiral crossover. On the other hand, the strangeness carrying degrees of freedom inside the quark gluon plasma can be described by a weakly interacting gas of quarks only for temperatures larger than twice the chiral crossover temperature. In the intermediate temperature window, these observables show considerably richer structures, indicative of the strongly interacting nature of the quark gluon plasma.

Antihypertensive effect of a fixed-dose combination of losartan/hydrochlorothiazide in patients with uncontrolled hypertension: a multicenter study.

BACKGROUND: Achieving adequate blood pressure (BP) control often requires more than one antihypertensive agent. The purpose of this study was to determine whether a fixed-dose formulation of losartan (LOS) plus hydrochlorothiazide (HCTZ) (LOS/HCTZ) is effective in achieving a greater BP lowering in patients with uncontrolled hypertension. METHODS: The study was a prospective, multicenter, observational trial exploring the antihypertensive effect of a single tablet of LOS 50 mg/HCTZ 12.5 mg. A total of 228 patients whose BP had previously been treated with more than one antihypertensive agents without having achieved BP goal below 130/80 mmHg enrolled in the study. RESULTS: A significant decrease in systolic and diastolic BP was observed in both clinic and home measurement after switching from the previous treatment to LOS/HCTZ. There was a significant decrease in both B-type natriuretic peptide (BNP) and urinary albumin creatinine (Cr) excretion ratio (ACR), especially in patients with elevated values. In contrast, there was a significant increase in serum Cr concentration in conjunction with a decrease in estimated glomerular filtration rate (eGFR). Overall serum uric acid (UA) concentration increased, whereas in patients with hyperuricemia there was a significant reduction in this value. CONCLUSION: Switching to LOS/HCTZ provides a greater reduction in clinic and home BP in patients with uncontrolled hypertension. This combination therapy may lead to cardio-, reno protection and improve UA metabolism.

A CMOS-based on-chip neural interface device equipped with integrated LED array for optogenetics.

A novel CMOS-based neural interface device equipped with an integrated micro light source array was proposed and demonstrated. Target application of the device is optogenetics. GaInN LED array formed on sapphire substrate was successfully assembled with a multifunctional CMOS image sensor which is capable of injecting current via any of the pixel. We demonstrated addressable LED operation with the present device. The device has advantages such as simultaneous multi-site stimulation and on-chip optical imaging, that are not available with previously reported LED array device for optogenetics.

IgE-dependent enhancement of Th2 cell-mediated allergic inflammation in the airways.

T helper 2 (Th2) cell-derived cytokines, including interleukin (IL)-4, IL-5 and IL-13, play important roles in causing allergic airway inflammation. In contrast to Th2 cells, however, the role of IgE and mast cells in inducing allergic airway inflammation is not understood fully. In the present study, we addressed this point using transgenic mice expressing trinitrophenyl (TNP)-specific IgE (TNP-IgE mice), which enable us to investigate the role of IgE without the influence of antigen-specific T cell activation and other immunoglobulins. When the corresponding antigen, TNP-BSA, was administered intranasally to TNP-IgE mice, a large number of CD4+ T cells were recruited into the airways. In contrast, TNP-BSA administration did not induce eosinophil recruitment into the airways or airway hyperreactivity. Furthermore, when ovalbumin (OVA)-specific Th2 cells were transferred to TNP-IgE mice and the mice were challenged with inhaled OVA, TNP-BSA administration increased OVA-specific T cell recruitment and then enhanced Th2 cell-mediated eosinophil recruitment into the airways. These results indicate that IgE-induced mast cell activation principally induces CD4+ T cell recruitment into the airways and thus plays an important role in enhancing Th2 cell-mediated eosinophilic airway inflammation by recruiting Th2 cells into the site of allergic inflammation.

Ligamentum flavum hematoma in the thoracic spine.

We report a case of a hematoma of ligamentum flavum at T11-12 in a 66-year-old man who presented with progressive weakness of the right foot and numbness of both legs. Past history was negative and no precipitating episode of lower back sprain or trauma. The resected T11 and T12 laminas showed old hematoma with degenerative changes in the ligamentum flavum. Hematoma occurring in the thoracic spine has never been reported previously.

Herniation of cervical intervertebral disc: immunohistochemical examination and measurement of nitric oxide production.

STUDY DESIGN: Surgically obtained cervical herniated intervertebral discs were examined histologically and immunohistochemically. The production of nitric oxide (NO) in the local tissue was examined using the electron spin resonance (ESR) method. OBJECTIVES: To investigate the local histologic and immunohistochemical changes in cervical disc herniation, including NO production, and to compare such changes with those in autopsy cases. SUMMARY OF BACKGROUND DATA: Very little is known about the histopathologic processes of cervical disc herniation. In addition, no information is available on the level of in vivo NO production in cervical disc herniation. METHODS: Thirty-six herniated cervical discs obtained from 31 patients were immunohistochemically examined for localization of blood vessels, matrix metalloproteinase (MMP)-3, and inducible NO synthetase (iNOS). We also compared the production of NO, measured by the ESR method, in eight specimens with that of five control discs obtained from fresh cadavers. RESULTS: The presence of herniated discs correlated with the degeneration of cartilaginous endplate and torn anulus fibrosus. Formation of new blood vessels around the herniated discs was detected, using von Willebrand factor antibody, in seven uncontained hernias and 20 contained hernias. Immunohistochemical studies showed the presence of cells positive for MMP-3 (chondrocytes), iNOS (chondrocytes and granulation tissue) in cervical disc hernias. ESR analysis showed a significantly higher NO production in herniated cervical discs than in disc samples of fresh cadavers. CONCLUSIONS: Herniated cervical intervertebral disc is characterized by the presence of an inflammatory process associated with neovascularization and increased expression of MMP-3. Production of NO was markedly high in both contained- and uncontained-type hernias.

Polymorphism of tumor necrosis factor-beta and alcohol dehydrogenase genes and alcoholic brain atrophy in Japanese patients.

BACKGROUND: Alcohol abuse can induce brain atrophy, but it only occurs in some alcoholics. Many inflammatory cytokines such as tumor necrosis factor (TNF) are produced rapidly in the brain by experimental or clinical injury. METHOD: To investigate whether genetic polymorphism of TNF was related to alcoholic brain atrophy, we determined restriction fragment-length polymorphisms of the TNF-beta genes in 72 male alcoholics. Computed tomography was used to determine the severity of brain atrophy. RESULTS: Digestion with NcoI and MspI after polymerase chain reaction amplification showed that the TNFB1 allele frequency was significantly higher in patients with brain atrophy than in those without brain atrophy (chi2 = 10.20, p = 0.0034). A multivariate analysis that included age, total alcohol intake, ADH2 genotype, and TNF-beta genotype showed that the ADH21/21 genotype and TNFB1/B1 genotype are independently associated with alcoholic brain atrophy. These findings suggest that the TNFB1 allele may be associated with alcoholic brain atrophy.

Relationships among bone mineral densities, static alignment and dynamic load in patients with medial compartment knee osteoarthritis.

OBJECTIVE: To investigate the relationships among bone mineral density (BMD), static alignment and the adduction moment of the knee in patients with tibiofemoral osteoarthritis (OA). METHODS: Sixty-nine patients with medial compartment knee OA underwent radiographic evaluation, gait analysis and BMD measurements at the proximal tibia and lumbar spine. RESULTS: The bone mineral distribution of the medial to lateral part of the proximal tibia correlated significantly with the peak knee adduction moment and the mechanical axis. Furthermore, the adduction moment correlated significantly with the mechanical axis. However, the BMD of the lumbar spine and the bone mineral distribution of the posterior to anterior part of the proximal tibia did not correlate with any other measurement. CONCLUSIONS: Our results suggest that the bone mineral distribution of the proximal tibia is directly affected but lumbar BMD is not influenced by the local mechanical stress around the knee with medial compartment OA.

Gait analysis of spastic walking in patients with cervical compressive myelopathy.

To assess neurological status and to evaluate the effect of surgical decompression in patients with cervical myelopathy, we performed computerized gait analysis in 24 patients with cervical compressive myelopathy who showed spastic walking. Gait analysis was repeated during neurological follow-up that averaged 32.4 months. The gait pattern in patients with severe myelopathy was characterized by hyperextension of the knee in the stance phase without plantar flexion of the ankle in the swing phase, significantly reduced walking speed and step length, prolonged stance phase duration and decreased single-stance phase duration, and increased step width. The angle of flexion of the knee joint in the stance phase was significantly correlated with the Japanese Orthopaedic Association (JOA) score. Postoperative neurological improvement was associated with increased walking speed and decreased extension angle of the knee joint (single-stance phase and swing phase). Postoperatively, 12 patients had normalized extension of the knee in stance phase and their walking speed, cadence, stance phase duration, and single-stance phase duration, as well as step length and width, showed nonsignificant differences from these parameters in healthy controls. Our results show that kinesiological gait analysis is clinically useful for the functional assessment of the severity of spastic walking in cervical myelopathy.

Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone.

We examined immunohistochemically the fracture repair process in rat tibial bone using antibodies to PCNA, BMP2, TGF-beta 1,-2,-3, TGF-beta R1,-R2, bFGF, bFGFR, PDGF, VEGF, and S-100. The peak level of cell proliferation as revealed by PCNA labelling appeared first in primitive mesenchymal cells and inflammatory cells at the fracture edges and neighboring periosteum at 2-days after fracture, followed by the peaks of periosteal primitive fibroblasts and chondroblasts, which appeared at fracture edges at 3- and 4-days after fracture, respectively. BMP2 was weakly positive in primitive mesenchymal cells, osteoblasts and chondroblasts. At 3-days post-fracture, periosteal osteoblasts produced osteoid tissue and callus with marrow spaces lined by osteoblasts and osteoclasts, and all primitive mesenchymal cells and osteoblasts were positive for TGF-beta 1,-2,-3, and TGF-beta R1,-R2. They were also positive for vascular growth factors bFGF, FGFR and PDGF, but negative for VEGF, and the peak of PCNA labelling of vascular endothelial cells in the marrow space was delayed to 4-days after fracture. Chondroblasts at fracture edges produced hypertrophic chondrocytes at 5-days after fracture and they were positive for TGF-beta 1,-2,-3, and TGF-beta R1,-R2. Primitive chondroblasts were positive for vascular growth factors VEGF as well as bFGF, FGFR, and the peak of PCNA labelling of vascular endothelial cells in the cartilage was at 5-days after fracture. Hypertrophic chondrocytes were also positive for these growth factors but negative for bFGF and bFGFR. S-100 protein-induced calcification was only positive on chondroblasts and hypertrophic chondrocytes. At 7-days after fracture, bone began to be formed from the cartilage at fracture edges, by a process similar to bone formation in the growth plate. Enchondral ossification established a bridge between both fracture edges and periosteal membranous ossification encompassed the fracture site like a sheath at 14 day after fracture. Our study of fracture repair of bone indicates that this process is complex and occurs through various steps involving various growth factors.

Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients.

OBJECTIVE: Cytokine interleukin-1beta plays a central role in the inflammation process. Serum levels of IL-1beta are elevated in patients with alcoholic liver disease (ALD), especially in those with cirrhosis and alcoholic hepatitis. Recently, the presence of genetic polymorphisms of this cytokine was confirmed. The aim of this study was to determine whether IL-1beta polymorphisms are associated with the development of ALD. METHODS: We examined the frequency of two polymorphisms in the IL-1beta gene located in promoter -511 and exon 5 +3953 locus by restriction fragment length polymorphisms in 142 male patients with ALD, 30 heavy drinkers without ALD, and 218 healthy controls. RESULTS: The carriers of -511 IL-1beta allele 2 were present significantly more often in patients with alcoholic cirrhosis than in those with noncirrhotic ALD (p = 0.026), heavy drinkers without ALD (p = 0.001), and healthy controls (p = 0.032). The frequencies of allele 2 and heterozygotes of +3953 polymorphism were both significantly higher in heavy drinkers without ALD than in patients with ALD (allele, p = 0.030; genotype, p = 0.027) and healthy controls (allele, p = 0.047; genotype, p = 0.043). The haplotype, IL-1beta -511 allele 2/+3953 allele 1 was associated with the development of alcoholic cirrhosis (p < 0.05). CONCLUSIONS: These results suggest that IL-1beta polymorphisms may be related to the development of ALD in Japanese alcoholics.

Spontaneous remission of a solitary intraspinal synovial cyst of the lumbar spine.

We report on a 15-year-old boy in whom a spontaneous remission of a symptomatic synovial cyst, possibly emanating from the L4-5 facet joint, was noted. The medical history suggested that sport-related overactivity and/or minor trauma was the underlying cause. Conservative treatment for several months may be one treatment option if the cyst wall is not calcified and the symptoms and signs related to radiculopathy show a gradual decrease.

Potential usefulness of 18F-2-fluoro-deoxy-D-glucose positron emission tomography in cervical compressive myelopathy.

STUDY DESIGN: This case study describes the usefulness of high-resolution 18F-2-fluoro-deoxy-D-glucose (18FDG)-positron emission tomography (PET) for metabolic neuroimaging of the cervical spinal cord in patients with compressive myelopathy. OBJECTIVE: To examine whether 18FDG-PET imaging could visualize deterioration of cervical spinal cord function associated with a variable degree of compression and to determine its potential usefulness during assessment of myelopathy. SUMMARY OF BACKGROUND DATA: A few studies have described the use of 18FDG-PET imaging in cervical cord diseases, but visualization of the cervical spinal cord before and after surgical decompression for compressive myelopathy has not been reported. The potential usefulness of 18FDG-PET imaging for assessment of the function of compressed cervical cord has not been discussed previously. METHODS: An 18FDG-PET scan was performed before and after surgery in seven patients with cervical compressive myelopathy. The correlation between the metabolic rate of glucose of the cervical spinal cord and neurologic scores was evaluated. The metabolic rate of glucose in different vertebral levels was also measured. RESULTS: Preoperative metabolic rate of glucose was high in two patients but low in the other five. At the time of the second postoperative examination, metabolic rate of glucose was higher in six of the seven patients, and the increase was associated with neurologic improvement. Use of 18FDG was not related to changes in signal intensities on T2-weighted magnetic resonance images. The metabolic rate of glucose decreased at the affected vertebral level in four patients, increased in two, and did not change in one, relative to the unaffected levels. CONCLUSIONS: High-resolution 18FDG-PET neuroimaging may provide clinically useful qualitative and quantitative estimation of impaired metabolic activity of the compromised cervical spinal cord in compressive myelopathy. 18FDG-PET images may also offer additional information related to neuronal dysfunction induced by mechanical compression.

Histological investigation of spinal cord lesions in the spinal hyperostotic mouse (twy/twy): morphological changes in anterior horn cells and immunoreactivity to neurotropic factors.

We examined the morphology of spinal accessory motoneurons and immunoreactivity to neurotrophins, brain-derived neurotropic factor (BDNF) and neurotrophin (NT)-3, as well as the presence of reactive astrocytosis in 70 tiptoe walking Yoshimura (twy) mice that develop calcification at C1-C2 vertebral level compressing the spinal cord. At the level of compression, the area of neuronal soma and total length of dendrites of wheat germ agglutinin-horseradish peroxidase (WGA-HRP)-labelled accessory motoneurons in the medial cell pool decreased significantly with decrement in motoneuron population, relative to the control. In contrast, at sites rostral to the compressive lesion, a significant enlargement of the neuron soma and dendritic elongation were noted, associated with increased motoneuron population and decreased transverse area of the cord at the level of compression. At this site, enhanced BDNF and NT-3 immunoreactivities were evident in the anterior horn cells. In mice with a more severe degree of compression, astrocyte-like cells showing BDNF immunoreactivity became abundant and axons in the anterior column demonstrated a marked NT-3 immunoreactivity. Our results suggest increased functional activity of anterior horn cells at levels rostra] to the site of compression. We speculate that the presence of BDNF and NT-3 in neurons and astrocyte-like cells is proportionate to the severity of chronic mechanical compression and may contribute to the heterotropic neuronal reserve and survival.